1. Field of the Invention
The present invention provides a chemical acylation process and, in particular, an aqueous acylation process for the preparation of the antibiotic, cefepime dihydrochloride hydrate which is also known as 7-[2-(2-aminothiazol-4-yl)-2-(Z)-methoxyiminoacetamido]-3-[(1-methyl-1-pyr rolidinio)-methyl]ceph-3-em-4-carboxylate. The present invention also provides a stable, crystalline salt of the syn-isomer of a thiazolyl intermediate and a process for the preparation thereof which may be used in the preparation of useful broad spectrum antibacterial agents.
2. Background Art
A large number of cephalosporin antibiotics are known which contain a 2-(2-aminothiazol-4-yl)-(Z)-2-methoxyimino acetic acid side chain which is coupled to the 7-amino group of a cephalosporanic acid by well-known acylation procedures. In most instances, it is necessary to protect the amino moiety and activate the carboxylic acid of the side chain as part of the acylation procedure. Consequently, the art discloses a large number of amino-protecting groups for the 2-amino group of the thiazole ring and a large number of activating groups for the carboxylic acid. The search for newer protecting groups and activating groups to produce the desired antibiotic is still the subject of numerous publications in view of the costs and toxicities associated with certain activating groups. Therefore, there is still a need in the preparation of useful broad spectrum antibiotics for a simple, stable, crystalline, economical, and non-toxic side chain having the desired geometric (Z)-isomer which can be readily coupled to the 7-amino group of the cephalosporin nucleus. The following is representative of some of the thiazole side chain art.
In U.S. Pat. No. 4,203,899 to Ochiai, et al., issued May 20, 1980, there is disclosed compounds of the Formula ##STR1## wherein R.sup.1 represents amino, protected amino, hydroxyl, or protected hydroxyl; R.sup.5 represents hydroxyl or protected hydroxyl; and W represents hydroxyl, C.sub.1-4 alkoxy, halogen, or OM wherein M is an alkali metal.
U.K. Patent Application GB-2,144,424, published Mar. 6, 1985, discloses the preparation of a series of pyridinium cephalosporin derivatives by various methods, including the use of the compound of Formula ##STR2## or a salt thereof wherein R.sup.1 denotes a hydrogen or halogen atom; R.sup.2 denotes a hydrogen atom or a C.sub.1-6 alkyl radical, and R.sup.4 represents hydrogen or an amino protective group, or with an activated derivative of this compound.
European Patent Application EP-160,546, published Nov. 6, 1985, also discloses the preparation of a series of cephalosporin compounds by various methods, including the use of the substituted oxyiminothiazolyl acetic acid compounds of Formula ##STR3## or a reactive derivative thereof, wherein R.sup.8 represents a hydrogen atom or a protective group for an amino group. Suitable examples of such reactive derivatives which are disclosed are mixed acid anhydrides, acid anhydrides, acid halides, active esters, active amides, and acid azides.
In U.S. Pat. No. 4,385,181 to Farge, et al., issued May 24, 1983, there is disclosed thioloesters of the Formula ##STR4## wherein R' represents hydrogen or a protecting radical, R.sup.o represents hydrogen, alkyl, vinyl, cyanomethyl, or a protecting radical, and R represents alkyl, L-2-amino-2-carboxyethyl, phenyl, or a large number of various heterocyclic radicals listed in columns 4 to 8, as well as their syn- and anti-isomers and mixtures thereof.
In addition to the above-cited references, there exists a large number of references which disclose various protecting groups for the 2-amino substituent and an even larger number of activating groups/leaving groups of the carboxylic acid moiety which may be used in the acylation of a 7-amino cephalosporin compound.
However, the most relevant art is Czechoslovak Patent No. 238,950, published Mar. 16, 1987, [Chemical Abstracts, Vol. 110, p. 544 (1989)] which discloses the compound of the instant invention having the Formula ##STR5## wherein the compound is alleged to have the syn configuration. The only evidence presented for the product in the patent is a chlorine content of 99% to 100.5% of the theoretical value.
In connection with work on the development Of new synthetic methods for the production of antibiotics, the present inventors, as well as others in the art, have felt the need for simple, convenient, economical, crystalline, stable, and non-toxic starting materials for use in the manufacture of antibiotics. Initial attempts to prepare and use the acid chloride of 2-(2-aminothiazol-4-yl)-2-methoxyimino acetic acid without the use of protecting groups were unsuccessful. However, the present inventors have now found that the compound of the instant invention can be prepared under specifically defined reaction conditions. This finding was further confirmed by the present inventors when they could not reproduce the teachings of the above-cited Czechoslovak patent. The desired syn-isomer of the acid chloride hydrochloride, which is necessary to produce the desired antibiotic, could not be repeated. Furthermore, additional experiments confirmed that the teachings of the art did not produce the hydrochloride salt of the desired syn-isomer of the acid chloride substantially free of the anti-isomer and having a proton nuclear magnetic resonance spectrum (.sup.1 H NMR) as described herein.
The broad spectrum antibiotic cefepime is disclosed by Aburaki, et al, in U.S. Pat. No. 4,406,899, issued Sep. 27, 1983 and its preparation is described by two Reaction Schemes in which the reactants and products required the use of blocking and deblocking groups. In the reaction scheme actually exemplified, the product required a chromatographic purification step to separate the mixture of .DELTA..sup.2 and .DELTA..sup.3 isomers and the cefepime product thereby produced is in the zwitterion form. However, the zwitterion form of cefepime is unstable at room and elevated temperatures.
Murray A. Kaplan et al, in U.S. Pat. No. 4,910,301, issued Mar. 20, 1990, discloses temperature stable crystalline salts of cefepime in dry powder form having excellent room and superior elevated temperature stability compared to the zwitterion form of cefepime described by Aburaki et al, U.S. Pat. No. 4,406,899.
In U.S. Pat. No. 4,868,294, issued September 19, 1989, Brundidge et al, describe the preparation of 7-amino-3-[(1-methyl-1-pyrrolidinio)-methyl]ceph-3-em-4-carboxylate salts substantially free of the A.sup.2 isomer and their use in an aqueous acylation procedure to prepare the antibiotic cefepime as the sulfate salt.
In U.S. Pat No. 4,754,031, issued Jun. 28, 1988, Angerbauer et al, describe a process for the preparation of several cephalosporin antibiotics including cefepime in the zwitterion form. Although this process does not use protecting groups, it does use an anhydride for activation in an aqueous acylation reaction which requires chromatographic purification steps to give the zwitterion form of cefepime.
In U.S. Pat. No. 4,943,631, issued Jul. 24, 1990, Brian E. Looker describes an improved process for the preparation of the antibiotic cefepime as a hydriodide salt. The process controls the formation of the undesirable .DELTA..sup.2 isomer by employing a cephalosporin sulfoxide intermediate. However, the process described in the patent remains costly and inefficient since it introduces two additional steps to the prior art process and continues to use protecting groups which require blocking and deblocking procedures. Furthermore, the process requires the use of column chromatography as a purification method which is impractical on a manufacturing scale.
The preparation of the crystalline sulfate salt and zwitterion of cefepime which are described in the art use essentially the same aqueous acylation process and use various blocking and deblocking groups and active esters. In all instances, the preferred crystalline cefepime dihydrochloride hydrate form must be prepared via the purified zwitterion form of cefepime. Thus, there is a need to develop a simple, direct and cost effective acylation procedure which will avoid reaction steps to add and remove protecting groups, stereochemical controlling steps and chromatography procedures and, more importantly, an acylation procedure which will produce the desired antibiotic cefepime dihydrochloride hydrate which is substantially free of the anti-isomer and the .DELTA..sup.2 isomer.